福泰製藥 (VRTX) 2017 Q2 法說會逐字稿

Good evening. This is Michael Partridge, Vice President of Investor Relations for Vertex. Welcome to our second quarter 2017 financial results conference call. (Operator Instructions) This call is recorded, and a replay will be available later on our website.

晚安.這是 Vertex 公司投資者關係副總裁 Michael Partridge。歡迎參加我們2017年第二季財務業績電話會議。（操作員指示）本次通話將被錄音，稍後將在我們的網站上提供回放。

Dr. Jeff Leiden, Chairman and CEO; and Ian Smith, Chief Operating Officer and Chief Financial Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer, will join us for Q&A.

董事長兼執行長傑夫萊頓博士和營運長兼財務長伊恩史密斯將於今晚發表準備好的演講。首席商務官史都華·阿巴克爾將參加問答環節。

We will make forward-looking statements on this conference call. These statements are subject to the risks and uncertainties discussed in detail in today's press release, our 10-K and other filings with the Securities and Exchange Commission. These statements, including those regarding the ongoing development and commercialization of KALYDECO and ORKAMBI, Vertex's other cystic fibrosis programs and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. Information regarding our use of GAAP and non-GAAP financial measures and the reconciliation of GAAP to non-GAAP is available in the financial results press release. I would also refer you to Slide 3 on tonight's webcast.

我們將在本次電話會議上發表一些前瞻性聲明。這些聲明受到今天新聞稿、我們的 10-K 表格以及向美國證券交易委員會提交的其他文件中詳細討論的風險和不確定性的影響。這些聲明，包括有關 KALYDECO 和 ORKAMBI 的持續開發和商業化、Vertex 的其他囊性纖維化項目以及 Vertex 未來的財務業績的聲明，都是基於管理層目前的假設。實際結果和事件可能與此有重大差異。有關我們使用 GAAP 和非 GAAP 財務指標以及 GAAP 與非 GAAP 的調整的信息，請參閱財務業績新聞稿。我還想請您參考今晚網路直播的第三張投影片。

I will now turn the call over to Dr. Jeff Leiden.

現在我將把電話交給傑夫·萊頓博士。

Thanks, Michael. Good evening (inaudible). 2017 is an important year for Vertex, and we've made significant progress towards achieving our long-term vision of treating all people with CF. As we entered this year, we were focused on continuing to increase the number of people eligible for and being treated with our approved medicines as well as generating important data for multiple combination medicines across our CF pipeline.

謝謝你，麥可。晚上好（聽不清楚）。2017 年對 Vertex 來說是重要的一年，我們在實現治療所有囊性纖維化患者的長期願景方面取得了重大進展。今年年初，我們專注於繼續增加符合條件並接受我們已批准藥物治療的人數，以及為我們 CF 產品線中的多種組合藥物產生重要數據。

Let me briefly review our recent progress in meeting these objectives. First, the FDA recently approved KALYDECO for more than 900 people with CF ages 2 and older who have 1 of 23 residual function mutations, and we continue to work closely with the FDA to obtain approval for more than 600 additional people who have other residual function mutations responsive to KALYDECO. KALYDECO continues to be a transformative medicine and is now able to treat approximately 5,000 people with CF globally. Tonight, we are reiterating our KALYDECO revenue guidance.

讓我簡要回顧一下我們近期在實現這些目標方面所取得的進展。首先，FDA 最近批准 KALYDECO 用於 900 多名 2 歲及以上患有 CF 且攜帶 23 種殘餘功能突變之一的患者，我們將繼續與 FDA 密切合作，以獲得 600 多名其他對 KALYDECO 有反應的殘餘功能突變患者的批准。KALYDECO 繼續發揮變革性藥物的作用，目前已在全球範圍內治療約 5,000 名囊性纖維化患者。今晚，我們將重申 KALYDECO 的營收預期。

Second, we've now reached reimbursement agreements in Ireland and Italy for ORKAMBI in people ages 12 and older with 2 copies of the F508del mutation. We continue to discuss reimbursement with other countries, including France, the Netherlands and the United Kingdom and remain committed to expanding the eligibility for and access to ORKAMBI globally. Tonight, we also reiterated our guidance for ORKAMBI.

其次，我們現在已經與愛爾蘭和義大利就 ORKAMBI 的報銷協議達成一致，該協議適用於 12 歲及以上且攜帶 2 個 F508del 突變拷貝的人群。我們繼續與其他國家（包括法國、荷蘭和英國）討論報銷事宜，並致力於在全球範圍內擴大 ORKAMBI 的適用範圍和使用管道。今晚，我們也重申了我們對 ORKAMBI 的指導。

Third, based on the positive Phase III data we announced earlier this year, we recently submitted an NDA to the FDA and an MAA to the European Medicines Agency for the tezacaftor/ivacaftor combination in people with CF ages 12 and older. We anticipate acceptance of the NDA and the MAA later this year.

第三，基於我們今年稍早公佈的積極的 III 期數據，我們最近向美國食品藥品監督管理局 (FDA) 提交了 tezacaftor/ivacaftor 組合療法的新藥申請 (NDA)，並向歐洲藥品管理局提交了上市許可申請 (MAA)，用於治療 12 歲及以上患有囊性纖維化的人群。我們預計將於今年稍後接受 NDA 和 MAA。

Fourth, we recently shared positive Phase I and Phase II results from 3 of our triple combination regimens in people with CF who have at least 1 F508del mutation. These results included the first data to demonstrate the potential to treat the underlying cause of CF in het/min patients who have a severe and difficult to treat type of this disease. They also demonstrated that the addition of a next-generation corrector to tezacaftor and ivacaftor significantly increases FEV1 in F508del homozygous patients.

第四，我們最近分享了 3 種三聯療法在至少攜帶 1 個 F508del 突變的 CF 患者中的 I 期和 II 期積極結果。這些結果包括第一個證明有可能治療患有嚴重且難以治療的 CF 類型的 het/min 患者的 CF 根本病因的數據。他們還證明，在 tezacaftor 和 ivacaftor 中添加下一代矯正劑可顯著提高 F508del 純合子患者的 FEV1。

Throughout the rest of this year, we will be evaluating additional data from these and other studies, and I look forward to updating you on our plans for pivotal development of our triple combination regimens that may have the potential to treat up to 90% of CF patients. We expect to begin pivotal development in the first half of 2018 for 1 or 2 of our 4 next-generation correctors.

在今年剩餘的時間裡，我們將評估這些研究和其他研究的更多數據，我期待向大家匯報我們三聯療法關鍵性開發計劃的最新進展，該療法有可能治療高達 90% 的囊性纖維化患者。我們預計將於 2018 年上半年開始對 4 款下一代校正器中的 1 或 2 款進行關鍵性開發。

And lastly, earlier this week, we added CTP-656 to our pipeline of CF medicines through completing our asset purchase agreement with Concert Pharmaceuticals. CTP-656 has the potential to be used as part of future once-daily combination regimens that treat the underlying cause of CF, and we are already working to integrate the potentiator into one of our triple combination regimens.

最後，在本週早些時候，我們透過與 Concert Pharmaceuticals 完成資產收購協議，將 CTP-656 添加到我們的 CF 藥物研發管線中。CTP-656 有潛力成為未來每日一次聯合治療方案的一部分，用於治療 CF 的根本病因，我們已經在努力將該增強劑整合到我們的三重聯合治療方案中。

Based on our significant progress this year, we are well positioned to achieve our long-standing goal to create medicines that fundamentally alter the progression of CF for all patients, and in doing so, meet our financial goal of delivering sustainable long-term revenue and earnings growth for Vertex.

基於我們今年取得的重大進展，我們完全有能力實現我們長期以來的目標，即為所有囊性纖維化患者研發出能夠從根本上改變疾病進程的藥物，並在此過程中實現我們的財務目標，即為 Vertex 帶來可持續的長期收入和盈利增長。

With that, I'll now turn the call over to Ian to discuss our financials.

接下來，我將把電話交給伊恩，讓他來討論我們的財務狀況。

Thanks, Jeff, and good evening to everyone. Tonight, I will discuss the key aspects of our second quarter 2017 financials, and I will also review our 2017 full year financial guidance.

謝謝你，傑夫，大家晚上好。今晚，我將討論我們 2017 年第二季財務狀況的關鍵方面，並回顧我們 2017 年全年財務預期。

Revenues first. Total CF product revenues of $514 million in the second quarter of 2017 represents a 21% increase compared to the $426 million we recorded in the second quarter of 2016 and a $33 million increase compared to the $481 million we recorded in the first quarter of 2017. We continue to see revenue growth as we treat more patients with our approved medicines.

收入優先。2017 年第二季 CF 產品總營收為 5.14 億美元，比 2016 年第二季的 4.26 億美元成長了 21%，比 2017 年第一季的 4.81 億美元成長了 3,300 萬美元。隨著我們使用核准藥物治療更多患者，我們的收入也持續成長。

For ORKAMBI, we reported second quarter 2017 product revenues of approximately $324 million, an increase of $29 million compared to the first quarter of 2017. This increase was driven by continued uptake of the medicine globally as well as the timing of both patient and pharmacy orders of approximately $10 million in advance of the Fourth of July holiday. These shipments will likely impact revenues in the third quarter of 2017.

ORKAMBI 2017 年第二季產品營收約為 3.24 億美元，比 2017 年第一季增加了 2,900 萬美元。這一增長是由於該藥物在全球範圍內的持續普及，以及在7月4日假期前夕，患者和藥房訂購了價值約1000萬美元的藥品。這些出貨量可能會對 2017 年第三季的營收產生影響。

Second quarter KALYDECO sales were $190 million compared to $186 million for the first quarter of 2017. We estimate there was approximately $5 million of inventory stocking at quarter end in advance of July Fourth holiday.

KALYDECO 第二季銷售額為 1.9 億美元，而 2017 年第一季為 1.86 億美元。我們估計，在7月4日假期前，季度末的庫存價值約為500萬美元。

Our second quarter 2017 non-GAAP combined R&D and SG&A expenses were $333 million compared to $306 million in the second quarter of 2016 and compared to $313 million in the first quarter of 2017. These increases are primarily due to the continued acceleration and broad advancement of our CF medicines in development and in particular, our portfolio of triple combination regimens. This revenue expense profile resulted in a non-GAAP net profit for the second quarter of 2017 of $99 million or $0.39 per diluted share compared to non-GAAP net profit of $58 million or $0.24 per diluted share for the second quarter of 2016 and compared to $101 million or $0.41 per diluted share for the first quarter of 2017. The significant growth year-over-year in net profit was largely driven by the strong growth in the total CF product revenues. During the second quarter of 2017, the company generated significant cash flow and ended the quarter with approximately $1.67 billion in cash, cash equivalents and marketable securities.

2017 年第二季非 GAAP 合併研發及銷售、一般及行政費用為 3.33 億美元，而 2016 年第二季為 3.06 億美元，2017 年第一季為 3.13 億美元。這些成長主要歸功於我們在 CF 藥物研發方面的持續加速和廣泛進步，特別是我們的三合一療法產品組合。根據此收入支出狀況，2017 年第二季非 GAAP 淨利為 9,900 萬美元，即每股攤薄收益 0.39 美元，而 2016 年第二季非 GAAP 淨利為 5,800 萬美元，即每股攤薄收益 0.24 美元，2017 年第一季非 GAAP 淨收益為 1.001 億美元，即每股盈餘 1.01 億淨收益。淨利年增率顯著，主要得益於CF產品總收入的強勁成長。2017 年第二季度，該公司產生了可觀的現金流，季末持有約 16.7 億美元的現金、現金等價物和有價證券。

Now turning to our full year financial guidance. We continue to expect total CF product revenues of $1.84 billion to $2.07 billion in 2017. For ORKAMBI, we continue to expect $1.1 billion to $1.3 billion in net product revenues. Our actual revenues will be determined by the continued uptake of ORKAMBI in the markets where it's reimbursed as well as the completion of additional reimbursement agreements throughout Europe. If we are successful in gaining reimbursement in France by the end of 2017, it would be a large contributor to our revenue growth. There continues to be uncertainty as to the timing of when these discussions will be completed.

接下來，我們來看看全年財務預期。我們仍預期 2017 年 CF 產品總營收將達到 18.4 億至 20.7 億美元。對於 ORKAMBI，我們仍然預計其淨產品收入為 11 億美元至 13 億美元。我們的實際收入將取決於 ORKAMBI 在已報銷市場的持續普及情況，以及在整個歐洲完成的額外報銷協議。如果我們能在 2017 年底前成功獲得法國的報銷，這將大大促進我們的收入成長。這些討論何時完成仍存在不確定性。

As to KALYDECO, we continue to expect $740 million to $770 million in net product revenues, which includes the recent approval in patients with residual function mutations. We continue to have productive discussions with the FDA to obtain approval for more than 600 people who have other residual function mutations responsive to KALYDECO.

至於 KALYDECO，我們仍然預計其淨產品收入為 7.4 億美元至 7.7 億美元，其中包括最近獲準用於治療具有殘餘功能突變的患者。我們繼續與 FDA 進行富有成效的討論，以獲得批准，使 600 多名對 KALYDECO 有反應的其他殘餘功能突變患者能夠接受治療。

Now to operating expenses. We have made significant investments in generating compelling data across our CF pipeline this year, and we now expect combined non-GAAP R&D and SG&A expenses of $1.33 billion to $1.36 billion for 2017. This updated guidance reflects the progression of our CF portfolio, including the acceleration of Phase II studies for VX-659 and VX-445. Preparation for pivotal studies for our portfolio of triple combination regimens and investment to develop CTP-656 is part of future triple combination regimens.

接下來是營運費用。今年，我們在CF產品線中投入了大量資金來產生引人注目的數據，我們現在預計2017年非GAAP研發和銷售、管理及行政費用合計為13.3億美元至13.6億美元。此次更新的指導意見反映了我們 CF 產品組合的進展，包括加速推進 VX-659 和 VX-445 的 II 期研究。為我們三聯療法組合的關鍵性研究做準備，並投資開發 CTP-656，這是未來三聯療法的一部分。

With our continued revenue growth, the management of our operating expenses, we are well on track to deliver a financial profile that includes high operating margins and sustainable earnings growth. With that, I will open up the line to questions.

憑藉持續的收入成長和對營運費用的有效控制，我們有望實現高營運利潤率和可持續獲利成長的財務狀況。接下來，我將開放提問環節。

(Operator Instructions) And our first question comes from the line of Matthew Harrison with Morgan Stanley.

（操作員說明）我們的第一個問題來自摩根士丹利的馬修·哈里森。

I guess, I'd just like to ask about the progression of pricing and reimbursement in Europe. You've obviously made some progress with some countries and yet some of the larger ones, including France, seem to be taking longer. Can you just talk about which of these things you're willing -- what items are still needing to be discussed and I guess, what we should think about in terms of that? And broadly, I guess, the nature of the question here is you've obviously got ORKAMBI now, but there's visibility towards tez/iva and then triple combos. And did that influence any of the conversation and perhaps take long -- longer to complete?

我想問一下歐洲的定價和報銷情況的發展。顯然，你們在一些國家取得了一些進展，但包括法國在內的一些大國似乎進展較慢。您能否談談您願意討論哪些方面—還有哪些事項需要討論，以及我們應該如何考慮這些問題？總的來說，我認為，這裡問題的本質是，你現在顯然有了 ORKAMBI，但 tez/iva 和三連擊也逐漸被看好。這是否對談話內容產生了影響，導致談話時間延長？

Great. Thanks, Matt. It's Stuart here. I'll try and address your question. It's got a number of different elements to it. As you say, we have made good progress in the first half of this year, reaching pricing and reimbursement agreements in Germany, Ireland, Italy, Austria, Luxembourg and Denmark. And as you said, we're in active negotiations with other countries, including France, the U.K. and the Netherlands. Where we are in those discussions, I'll refer you back to the comments we've made previously. These discussions tend to have 3 phases. There's a clinical benefit assessment, a pharmacoeconomic assessment, and then you're into the pricing discussions. And we're through those first 2. There's really no debate in those markets in Europe about the clinical benefit of ORKAMBI. We're really in the pricing and reimbursement discussions. And as Ian mentioned in his prepared remarks, unfortunately, the exact timing of when those are going to conclude is uncertain just because they're not directly within our control. As to the potential impact of newer agents in development on those discussions, what I'd say to you is that we're very pleased that in Ireland and Italy, where we reached agreements in May after the tez/iva data was available, those countries still saw fit to do what we think is the right thing, make a transformative medicine like ORKAMBI available to patients as soon as possible because it treats the underlying cause of the disease. And we know, therefore, that it's important for patients to be treated as early as possible, and we're certainly going to be continuing to make that case to the existing authorities who are still not providing access for patients in their countries.

偉大的。謝謝你，馬特。我是史都華。我會盡量回答你的問題。它包含許多不同的元素。正如您所說，今年上半年我們取得了良好進展，與德國、愛爾蘭、義大利、奧地利、盧森堡和丹麥達成了定價和報銷協議。正如你所說，我們正在與其他國家積極進行談判，包括法國、英國和荷蘭。關於我們目前討論的進展，我建議大家回顧一下我們之前發表的評論。這些討論通常分為三個階段。首先要進行臨床獲益評估、藥物經濟學評估，才能進入定價討論階段。前兩個市場已經過去了。在歐洲的這些市場中，ORKAMBI 的臨床益處實際上沒有任何爭議。我們目前正在討論定價和報銷問題。正如伊恩在事先準備好的演講稿中提到的那樣，不幸的是，這些事情何時結束的確切時間尚不確定，因為它們不在我們的直接控制範圍內。至於正在研發的新藥可能對這些討論產生的影響，我想說的是，我們非常高興地看到，在愛爾蘭和意大利，我們在 tez/iva 數據公佈後於 5 月份達成了協議，這兩個國家仍然認為應該做我們認為正確的事情，盡快讓像 ORKAMBI 這樣的變革性藥物惠及患者，因為它治療的是疾病的根本原因。因此我們知道，儘早治療患者非常重要，我們當然會繼續向那些仍然不讓本國患者獲得治療的現有當局提出這一觀點。

And our next question comes from the line of the Geoff Meacham with Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

A couple questions for you. Obviously, with the data thus far in the triple, you can expand the addressable population, but I wanted to ask you about the nonsense mutation and some of the splicing mutations. I know clearly you guys have the alliance with CRISPR and -- to look at some of those, but maybe just talk a little bit about what the strategy is there. Do you have technologies in-house to look at more nonsense mutation patients? Or is it just going to focus on Delta F, single and double? And then I have a follow-up.

我有幾個問題想問你。顯然，根據目前為止三重數據，您可以擴大可尋址人群，但我想問您關於無義突變和一些剪接突變的問題。我知道你們與 CRISPR 有合作關係，也想了解其中的一些情況，但或許可以稍微談談這方面的策略是什麼。貴公司內部是否有相關技術研究更多無義突變患者？或者它只會專注於 Delta F，包括單倍和雙倍？然後我還有一個後續問題。

Yes, thanks, Geoff. This is Jeff Leiden. 2 parts to your questions. We actually do splice and nonsense quite differently. So as you know and as Ian said, I think, we're in very productive discussions with the FDA around the splice mutations. Most of those produce normal CFTR but much lower amounts, and our in vitro data and our clinical data has clearly shown that they respond to KALYDECO, and by the way, also to tez/iva. And so the imperative there is to get KALYDECO monotherapy approved for those patients as soon as possible and then follow that with tez/iva, and we're confident that we will be able to do that. So that's splice. Nonsense mutations, as you pointed out, are quite different. They're obviously not going to respond to CFTR modulators because there is no protein there. And we have several approaches there, the first of which is the ENaC inhibitors. So one of reasons we were interested in studying the ENaC inhibitors, that's VX-371, is because they, as you know, function by a different mechanism that doesn't require functional CFTR protein. And so we'll have a look at the first data, as you know, in the second half of this year, but that's sort of mechanism number one to get at the nonsense mutations. And as you pointed out, mechanisms 2, our genetic approaches such as CRISPR and Moderna, we're making some nice progress in cell lines. We do have cell assays that allow us to look at those in both HBE cells and other cells. And the key issue there is going to be delivery. I actually think that gene editing and the ability for RNA to make CFTR is a relatively straightforward problem. The top problem here is delivery, and we're working on that in parallel. And as we've said, we do think that's going to take a number of years to bring forward into the clinic.

是的，謝謝你，傑夫。這是傑夫·萊頓。你的問題分為兩個部分。實際上，我們對拼接和無意義的處理方式截然不同。如你所知，也正如伊恩所說，我認為，我們正在與 FDA 就剪接突變問題進行非常有成效的討論。大多數患者都能產生正常的 CFTR，但數量少很多。我們的體外數據和臨床數據清楚地表明，他們對 KALYDECO 有反應，順便說一句，對 tez/iva 也有反應。因此，當務之急是盡快批准 KALYDECO 單藥療法用於這些患者，然後再批准 tez/iva 療法，我們有信心做到這一點。這就是拼接。正如你所指出的，無義突​​變與此截然不同。顯然，它們不會對 CFTR 調節劑產生反應，因為那裡沒有蛋白質。我們對此有幾種方法，第一種是 ENaC 抑制劑。因此，我們對研究 ENaC 抑制劑（即 VX-371）感興趣的原因之一是，如您所知，它們的作用機制不同，不需要功能性 CFTR 蛋白。因此，正如你們所知，我們將在今年下半年查看第一批數據，但這是獲得無義突變的第一個機制。正如你所指出的，機制 2，我們的基因方法，如 CRISPR 和 Moderna，我們在細胞系方面取得了一些不錯的進展。我們確實有細胞檢測方法，可以讓我們觀察 HBE 細胞和其他細胞中的這些細胞。而關鍵問題在於交付。我其實認為基因編輯和 RNA 製造 CFTR 的能力是一個相對簡單的問題。目前最大的問題是交付，我們正在同步解決這個問題。正如我們所說，我們認為這需要數年時間才能在臨床上應用。

Okay. And a follow-up question more on the commercial side, and I've asked you guys this a couple times before, but I just want to see if there's any update. Clearly, the market is U.S., Western Europe and Australia. But I wanted to see -- I think at one point, you guys had talked about opening an office down in Latin America or other countries that maybe have a founder effect, where you have populations that are well beyond the 70,000 that everyone puts up as the number. So is there -- maybe just help us with kind of where you are with that kind of more the global piece.

好的。還有一個關於商業方面的後續問題，我之前也問過你們幾次，但我只是想看看有沒有什麼新的進展。顯然，目標市場是美國、西歐和澳洲。但我很想看看——我想你們曾經討論過在拉丁美洲或其他可能存在創始人效應的國家開設辦事處，這些國家的人口遠遠超過大家所說的 7 萬。所以，您能否幫我們說說您目前在全球層面的情況？

Yes, Geoff. You're correct. We have established an office in São Paulo in Brazil as a potential sort of regional hub for Latin America. And you're right, there are numbers of patients in there. The level of newborn screening and the maturity of registries there is perhaps, as you might expect, not quite as advanced as it is here in the U.S. and in parts of Western Europe. And so the exact numbers of patients and indeed their specific genotypes, which we would anticipate being different in terms of distribution than it is in the U.S. and Europe, is not as well defined. And so much of our efforts over the last year or so has been working with the various CF societies and physicians in those markets to try and better understand the size of the potential patient population there and the specific genotypes that they have so that we can work out which of our medicines is best placed to help those patients out. So that's kind of the phase that we're at there. And I would say stay posted. We'll kind of update you as we make more progress from a commercial point of view there.

是的，傑夫。你說得對。我們在巴西聖保羅設立了辦事處，希望將其打造成為拉丁美洲的區域中心。你說得對，裡面確實有很多病人。那裡的新生兒篩檢水準和登記制度的成熟度，正如你可能預料到的那樣，可能不如美國和西歐部分地區那麼先進。因此，患者的確切人數，以及他們的具體基因型（我們預計分佈與美國和歐洲有所不同），尚不明確。在過去一年左右的時間裡，我們投入了大量精力與各個囊性纖維化協會和這些市場的醫生合作，以更好地了解當地潛在患者群體的規模以及他們的具體基因型，以便我們能夠確定哪種藥物最適合幫助這些患者。所以，我們目前就處於這個階段。我建議大家繼續關注。從商業角度來看，我們會隨著進展的增加及時向您報告。

And from a regulatory point of view, Geoff, it is our intention to go ahead and get these products registered there. There's a very formal way to do that, and we're well into that process.

從監管角度來看，Geoff，我們打算繼續推動這些產品的註冊工作。這件事有非常正式的流程，我們已經深入到這個流程了。

And our next question comes from the line of Terence Flynn with Goldman Sachs.

我們的下一個問題來自高盛的 Terence Flynn。

Was just wondering if you guys could comment on thoughts on uptake of tez/iva into the F508del homozygous patients with low baseline function. I know that it's been an area where there was some concern around use of ORKAMBI. Do you think tez/iva will be used there? Or do you think those patients would most likely wait until the triple combo is available?

想問各位能否就Tez/Iva在基線功能較低的F508del純合子患者中的應用發表一些看法。我知道，在使用 ORKAMBI 方面，一直存在一些擔憂。你認為那裡會使用 tez/iva 嗎？或者您認為這些患者很可能會等到三重療法上市後再進行治療？

Terence, it's Stuart here. Thanks for the question. Let me first talk a little bit more broadly about how we see tez/iva fitting in. We think tez/iva, because of the benefit/risk profile that it has, really has a great opportunity to allow us and physicians to treat more patients with CF. And that's because we think given the benefit/risk profile where we know the efficacy is very good, but also the safety and tolerability are also very good, that we think it will be applicable to a number of populations. Firstly, those who have discontinued ORKAMBI. Many of them discontinued for adverse events. We think that's a population that physicians and the patients themselves will be very keen to be retreated with a CFTR modulator. We also know there's patients who have never been treated with ORKAMBI, some of whom because the patient and/or physician were concerned about the benefit/risk profile of ORKAMBI. And then thirdly, outside the U.S., in particular, the residual function population where we don't have KALYDECO monotherapy approved is another population where based on the Phase III data that we showed in March with tezacaftor/ivacaftor, we believe will also be able to get additional patients on CFTR modulator. So overall for tez/iva, we see the biggest benefit for patients and physicians is being able to offer CFTR modulator to more people with the disease. In terms of exactly how it might be considered for those with low FEV1 is clearly, one of the major concerns physicians and patients have there was the bronchoconstriction side effect that we see from lumacaftor. We've known about that with lumacaftor for a while and as a result, we've been very diligent in looking at whether tezacaftor has that same property. We know from all of our Phase II data, from our Phase III data, from looking at both adverse events post dose spirometry that tez/iva does not have that same adverse event. And therefore, I think it's going to be a very popular option for patients with a low FEV1.

特倫斯，我是史都華。謝謝你的提問。首先，我想更廣泛地談談我們認為 tez/iva 如何融入其中。我們認為，由於 tez/iva 具有良好的益處/風險比，它確實有很大的機會讓我們和醫生能夠治療更多患有囊性纖維化的患者。這是因為我們認為，考慮到其益處/風險比，我們知道其療效非常好，安全性和耐受性也非常好，因此我們認為它將適用於許多人群。首先是那些已經停止使用 ORKAMBI 的人。其中許多產品因不良事件而停產。我們認為，對於這類人群，醫生和患者本人都會非常渴望使用 CFTR 調節劑進行治療。我們也知道有些患者從未接受過 ORKAMBI 治療，其中一些是因為患者和/或醫生擔心 ORKAMBI 的益處/風險比。第三，在美國以外，特別是對於殘餘功能人群（我們尚未批准 KALYDECO 單藥療法），根據我們在 3 月公佈的 tezacaftor/ivacaftor III 期數據，我們相信也能讓更多患者接受 CFTR 調節劑治療。因此，總的來說，對於 tez/iva 而言，我們認為對患者和醫生來說最大的好處是能夠為更多患有這種疾病的人提供 CFTR 調節劑。對於 FEV1 低的患者來說，究竟該如何考慮使用呢？顯然，醫生和病人最關心的問題之一就是 lumacaftor 引起的支氣管收縮副作用。我們早就知道lumacaftor具有這種特性，因此，我們一直在非常認真地研究tezacaftor是否也具有這種特性。我們從所有 II 期數據、III 期數據以及給藥後肺功能測定的不良事件中得知，tez/iva 沒有出現同樣的不良事件。因此，我認為對於 FEV1 較低的患者來說，這將是一個非常受歡迎的選擇。

And our next question comes from the line of Geoff Porges with Leerink Partners.

我們的下一個問題來自 Leerink Partners 的 Geoff Porges。

A couple strategy questions. First, Stuart, can you just talk about what success you're having with the full portfolio contracts and the more or less fixed pricing as you look ahead to now multiple generations, potentially 5 different product offerings over time? Is that a model that you think you can deploy globally? Or is it just in very selected markets? And what sort of reaction you were getting? And then secondly, Ian, your balance sheet is shaping up nicely, and we expect it to continue to improve and you're diversifying your portfolio across products. Is there a possibility that you might be able to take on some leverage and to sort of free up additional capital from your balance sheet in that way?

幾個策略方面的問題。首先，Stuart，你能否談談你目前在全套產品組合合約和相對固定的定價方面取得的成功情況，以及你展望未來幾代人，甚至隨著時間的推移，可能推出 5 種不同的產品？你認為這種模式可以在全球推廣嗎？還是僅限於極少數特定市場？當時你得到了什麼樣的回饋？其次，伊恩，你的資產負債表狀況良好，我們預計它會繼續改善，而且你的產品組合也不斷多元化。您是否有可能透過增加槓桿，從資產負債表中釋放出額外的資金？

So Geoff, I'll take your first question. So just for everybody's clarity on the call that, the approach that Geoff's referring to is an agreement that we reached earlier this year in Ireland where essentially we have an agreement, which is a long-term agreement, covers populations of patients, in this case, those who are homozygous to the F508del mutation or those who are one of the approved KALYDECO mutations and essentially looks at that patient population all the way down to age 0 and essentially includes in the agreement both the currently approved medicines, KALYDECO and ORKAMBI, will include patients for ORKAMBI when the indication is extended to lower age groups, but will also include new Vertex medicines in those specific patient populations. I would say to you, Geoff, that since that agreement was put in place and in particular, since both the tez/iva data and now the next-gen data, which makes it very clear to everybody how close we are to being able to develop medicines that treat the underlying cause of the disease in 90% of patients, there's been a lot of interest in discussing similar type of patient and/or portfolio contracts. So we're certainly very keen to be flexible. If that's what countries want to do, we're certainly, as we demonstrated in Ireland, very open to doing that. I personally believe it's a real win-win-win, that arrangement. It's a win for the Irish government, it's a win for Vertex and most importantly, it's a win for patients in Ireland. And so we're certainly very open to doing that kind of agreement in any country. We're in obviously early stages of discussions with newer countries along those lines and certainly, there's a lot of interest there. Whether we'll actually be able to get -- turn that interest into an agreement, time will tell. And I think Ian will handle the question on balance sheet.

那麼，傑夫，我先回答你的第一個問題。為了讓大家更清楚地了解通話內容，Geoff 提到的方法是我們今年稍早在愛爾蘭達成的協議。這項長期協議涵蓋了患者群體，在本例中，指的是攜帶 F508del 突變純合子或已獲批准的 KALYDECO 突變的患者。該協議涵蓋了從 0 歲到 1 歲的所有患者群體，包括目前已批准的藥物 KALYDECO 和 ORKAMBI。當 ORKAMBI 的適應症擴展到較低年齡層時，該協議也將涵蓋 ORKAMBI 的患者，同時也將 Vertex 公司針對這些特定患者群體推出的新藥納入其中。傑夫，我想對你說，自從那項協議達成以來，特別是自從tez/iva數據和現在的下一代數據公佈以來，這些數據清楚地表明，我們距離能夠開發出治療90%患者疾病根本原因的藥物還有多遠，因此，人們對討論類似的患者和/或產品組合合同表現出了濃厚的興趣。所以我們當然非常希望保持彈性。如果這是各國想要做的，我們當然也像我們在愛爾蘭所表明的那樣，對此持非常開放的態度。我個人認為，這種安排真是三贏的局面。這對愛爾蘭政府來說是一場勝利，對Vertex公司來說是一場勝利，最重要的是，這對愛爾蘭的患者來說是一場勝利。因此，我們當然非常願意在任何國家達成此類協議。我們顯然還處於與一些新興國家就此展開討論的早期階段，而且可以肯定的是，這些國家對此非常感興趣。我們是否真的能夠將這種興趣轉化為協議，時間會證明一切。我認為伊恩會處理資產負債表方面的問題。

So Geoff, first of all, to the cash, just to give a couple of points of where we are currently on our financial position. We have cash of close to $1.7 billion, and we are cash flow positive each quarter now and so that balance continues to increase. I'd also point out that we actually do already have a revolver facility. And so we have access to up to $800 million. It currently stands at $500 million, but we can expand it to $800 million. So on -- out of the $800 million debt capacity at the moment on the balance sheet that we have not yet drawn down on, plus the $1.7 billion of cash and a positive cash flow, we're in a very nice position to think about how we allocate that cash and how we apply it. Obviously, we're already making choices about our revenue stream as it grows to allocate internally, and that is going into R&D and it goes beyond just CF these days. It goes into other disease areas. And I'm sure before we finish this call, there will be a number of questions about how are we progressing beyond CF. And then as I've said on the call previously, that cash could now -- that's on the balance sheet and also the leverage and the increasing leverage and increasing availability of cash, we can apply outside the company. And we have 3 basic strategies there, and we're very active as shown actually by the announcement yesterday. So one of those strategies in the priority is still let's take a look at everything that's complementary in cystic fibrosis to our approach, and we actually just closed on the acquisition of CTP-656 yesterday. Another strategy is for us to look at other scientific footprints or scientific platforms or modalities and how they may allow us to treat diseases in different ways than just through small molecule approaches. And we've done both a Moderna and a CRISPR collaboration in the last year or so that have advanced our approaches in those areas. And then what is also emerging is how we may just have broadened our pipeline beyond CF with earlier-stage type deals that relate to asset acquisitions or targets and IP acquisitions and knowledge and assays and small M&A type ideas that we look at as well. We're very sensitive to looking at the capital structure of the company. We're still progressing, and I think our focus is on earlier-stage assets of high science and in disease areas that are consistent with cystic fibrosis.

傑夫，首先，關於現金方面，我先簡單介紹一下我們目前的財務狀況。我們擁有近 17 億美元的現金，而且現在每季現金流都是正的，因此現金餘額還在持續增加。我還要指出，我們實際上已經有一個左輪手槍製造廠了。因此，我們可以獲得高達 8 億美元的資金。目前金額為 5 億美元，但我們可以將其擴大到 8 億美元。因此，目前資產負債表上我們尚未動用的 8 億美元債務額度，加上 17 億美元的現金和正現金流，使我們處於非常有利的地位，可以考慮如何分配和運用這些現金。顯然，隨著收入來源的成長，我們已經在對收入進行內部分配，這些收入將投入研發，而如今研發的範疇已經遠遠超出了現金流。它還涉及其他疾病領域。我相信，在我們結束這通通話之前，肯定會有很多關於我們如何超越 CF 的問題。正如我之前在電話會議上所說，這些現金現在可以——這體現在資產負債表上，也體現在槓桿率、不斷增加的槓桿率和不斷增加的可用現金上——我們可以將其用於公司外部。我們在這方面有 3 個基本策略，正如昨天的公告所示，我們非常積極地採取行動。因此，優先策略之一仍然是讓我們看看在囊性纖維化方面與我們的方法互補的所有內容，而我們實際上昨天剛剛完成了對 CTP-656 的收購。另一種策略是，我們可以研究其他科學足跡、科學平台或模式，以及它們如何使我們能夠以不同於小分子方法的方式治療疾病。在過去一年左右的時間裡，我們與 Moderna 和 CRISPR 都開展了合作，這推進了我們在這些領域的研究方法。此外，我們還發現，我們可能已經將業務範圍擴展到 CF 以外的早期階段交易，這些交易涉及資產收購或目標、智慧財產權收購、知識和檢測以及我們正在考慮的小型併購類型的想法。我們非常關注公司的資本結構。我們仍在不斷進步，我認為我們的重點是處於早期階段的高科學資產以及與囊性纖維化一致的疾病領域。

Our next question comes from the line of Michael Yee with Jefferies.

我們的下一個問題來自 Jefferies 的 Michael Yee。

My question was on the Concert molecule, which of course, you just closed on yesterday. What are the next steps? How are you thinking about developing that? Could that be ready for one of the triples to start next year? What are the things you need to do there in discussion with the FDA? And the other question was in terms of your ongoing triples you have now in Phase II, how good do you feel about the therapeutic window in terms of going up and seen higher efficacy without the risk of any undue side effects?

我的問題是關於 Concert 分子的，當然，你們昨天剛剛結束了關於它的討論。下一步是什麼？您打算如何開發它？明年三支球隊中的一支能否開始比賽？在與FDA的討論中，你需要做些什麼？另一個問題是，關於您目前正在進行 II 期臨床試驗的三重療法，您對提高治療窗口、在不產生任何不必要的副作用的情況下獲得更高的療效有何看法？

Michael, it's Jeff. So I'll take both of those questions. So CTP-656, as you'll remember, is deuterated ivacaftor and the rationale there was to potentially get to a once-a-day regimen -- triple regimen because both 659 and 445 are consistent with once-daily dosing from what we know now about their PK; and of course, tezacaftor is consistent with once-daily dosing, whereas ivacaftor KALYDECO is not. It's a twice-a-day regimen. And so we're very pleased to close the transaction. We've already been actually working very hard on incorporating this molecule into a triple. It's a little early for me to give you a precise date. But if you ask me, could we come up with a triple regimen containing CTP-656 that is once a day and begin a pivotal trial in 2018, I'd say the answer from what I know today is likely yes. I want to emphasize that we're not going to wait for that certainly. It is our intention to give the best regimen to patients as quickly as possible. And so the first regimen, almost certainly we'll use ivacaftor KALYDECO and be a twice-a-day regimen and we'll follow that likely with a once-a-day regimen and we also have the opportunity to bridge back later to substitute in the ivacaftor. All of that, as you say, require some discussion with regulators, and it also requires a little more data on our part. We're certainly not going to jump into a Phase III trial with the ivacaftor until we have enough efficacy, safety, tolerability and PK data to make sure that we know the dose and we know how to put it together with the other agents. But again, we think that's a relatively short journey and that we could have such a regimen in pivotals next year. And then your second question, yes, the triple, and really the question was about therapeutic window. And as we said last week, one of the things that was most important for us to see in all 4 regimens actually was the very favorable safety and tolerability profile. And what that meant to us is that we could begin to extend dosing upwards. And so we're doing that, as you know, in at least 3 other regimens. So in 152, the initial data was at a 100- and 200-milligram dose. We are already extending that up to 300 milligrams, and those patients are being dosed. And so we'll see whether we can essentially bring more efficacy out of 152 with that same safety and tolerability profile. Some suggests that we may be able to because if you look back at that data, there does seem to be a clear dose response in FEV1 between 100 and 200. With 659, you'll remember we're at 120 b.i.d. And so the Phase II trial with 659, which is just beginning, will incorporate higher doses, up to 400 a day. And the 445 dosing will also go up. So with those 3 molecules, we are going to try to increase dose, looking for maximum benefit with a very favorable safety and tolerability profile. And as we said last week, we hope to have all that data converge towards the end of this year and early next year, and that will allow us to pick not only the best regimen or regimens, but the best doses.

麥可，我是傑夫。那我就回答這兩個問題吧。如您所記得，CTP-656 是氘代伊伐卡托，其原理是可能實現每日一次給藥方案——三聯給藥方案，因為根據我們現在對 659 和 445 的藥代動力學了解，它們都適合每日一次給藥；當然，特扎卡托適合每日一次給藥，而伊伐卡托 KALYDECO 則不適合。這是每天兩次的療程。因此，我們非常高興完成這筆交易。我們其實已經非常努力地將這種分子整合到三元體系中。現在給出確切日期還為時過早。但如果你問我，我們能否發展出一種含有 CTP-656 的三重療法，每天一次，並在 2018 年開始一項關鍵性試驗，根據我目前所了解的情況，我認為答案很可能是肯定的。我想強調的是，我們肯定不會等到那時。我們的目標是盡快為患者提供最佳治療方案。因此，第一個治療方案幾乎肯定會使用伊伐卡托（KALYDECO），每天服用兩次，之後可能會改為每天服用一次，而且我們以後還有機會過渡回伊伐卡托。正如你所說，所有這些都需要與監管機構進行一些討論，而且我們也需要提供更多的數據。在獲得足夠的療效、安全性、耐受性和藥物動力學數據，以確保我們知道劑量以及如何將其與其他藥物聯合使用之前，我們肯定不會貿然進行伊伐卡託的 III 期試驗。但我們再次認為這是一段相對較短的旅程，我們明年就可以在關鍵比賽中採用這樣的方案。然後是你的第二個問題，是的，三重問題，實際上這個問題是關於治療窗口的。正如我們上週所說，在所有 4 種治療方案中，我們最希望看到的是它們都非常良好的安全性和耐受性。這對我們來說意味著我們可以開始逐步增加劑量。所以，如你所知，我們至少在其他 3 個治療方案中也採用了這種方法。因此，在 152 年，初始數據是在 100 毫克和 200 毫克劑量下獲得的。我們已經將劑量提高到 300 毫克，並且正在給這些患者服用該藥物。因此，我們將看看能否在保持相同安全性和耐受性的基礎上，從 152 中獲得更多療效。有人認為我們或許能夠做到，因為回顧這些數據，FEV1 在 100 到 200 之間似乎確實存在明顯的劑量反應。659，你會記得我們每天有 120 次。因此，目前正在進行的 II 期試驗（劑量為 659）將採用更高的劑量，最高可達每天 400 毫克。445劑量也會增加。因此，我們將嘗試增加這 3 種分子的劑量，以期在獲得最大療效的同時，獲得非常良好的安全性和耐受性。正如我們上週所說，我們希望所有這些數據能在今年年底和明年年初匯合，這將使我們能夠不僅選擇最佳的治療方案，而且選擇最佳的劑量。

And our next question comes from the line of Phil Nadeau with Cowen and Company.

我們的下一個問題來自 Cowen and Company 的 Phil Nadeau。

It's actually kind of a follow-up to the last one and it's in data disclosure. I think Concert had guided to getting a monotherapy data for 656 out by the end of this year. Is that still likely now that's in your hands? And then second, Jeff, in your answer to the question that you just gave, it sounds like there'll be more disclosures on 152, 659 and 445 either late this year or early next. Is that a correct interpretation? Is that when we'll see the next data? Or are there interim releases that are possible?

實際上，這算是上一篇的後續，內容是關於數據揭露的。我認為 Concert 公司曾計劃在今年年底前公佈 656 的單藥治療數據。現在事情掌握在你手中，這種情況仍然有可能發生嗎？其次，傑夫，從你剛才提出的問題的回答來看，似乎今年晚些時候或明年年初會有更多關於 152、659 和 445 的信息披露。這種解讀正確嗎？那時我們就能看到下一批數據了嗎？或是否有可能進行過渡性發布？

Yes, thanks. So I'll take the first part and Ian, I think, can take the disclosure question. So with respect to CTP-656, the monotherapy, we're actually not planning to develop CTP-656 for monotherapy given that we believe that 90% of the patients will go on to a triple regimen. So we're really interested in this part of a once-a-day triple regimen. We will get some interesting, I think, PK data potentially from that study. But for us now, it's all about incorporating it into triple therapy and figuring out how to do that, which dose, making sure there's efficacy and a safety tolerability profile. It does require a lot of patience, but we will be doing that before we jump into pivotal trials. So I wouldn't focus on the monotherapy trials because I don't think that's where we're headed. Ian, maybe you can talk about disclosure?

好的，謝謝。所以我來回答第一部分，我想伊恩可以回答揭露問題。所以，就 CTP-656 單藥療法而言，我們實際上並不打算開發 CTP-656 單藥療法，因為我們相信 90% 的患者會接受三合一療法。所以我們對每天一次的三重療法中的這一部分非常感興趣。我認為，我們可能會從這項研究中獲得一些有趣的藥物動力學數據。但對我們來說，現在最重要的是將其納入三重療法，並弄清楚如何做到這一點，劑量是多少，確保療效和安全性耐受性。這確實需要很大的耐心，但我們會在進行關鍵性試驗之前做好這一點。所以我不會把重點放在單藥治療試驗上，因為我認為那不是我們未來的發展方向。伊恩，或許你可以談談資訊揭露的問題？

And Phil, as we disclosed a couple weeks ago, we're looking at our next-generation triple combination as a portfolio of medicines. And given we are choosing to complete each one of the Phase II studies of each molecule, we see our next disclosure is when we've completed that -- all the studies in Phase II. So when we completed the Phase II for 440, 152, 659 and 445, we anticipate that being early 2018, we'll be able to not only give you the data, we'll also be able to tell you how we're thinking about which molecule we're taking into Phase III in the first half of 2018. So we continue to view it as a portfolio, so we'd like to keep it to a portfolio disclosure and we anticipate that being early '18.

菲爾，正如我們幾週前所透露的那樣，我們正在將下一代三聯療法視為一系列藥物。鑑於我們選擇完成每種分子的 II 期研究，我們認為下一次揭露將在我們完成所有 II 期研究之後進行。因此，當我們完成 440、152、659 和 445 的 II 期臨床試驗後，我們預計在 2018 年初，我們不僅能夠向您提供數據，還能告訴您我們正在考慮在 2018 年上半年將哪個分子納入 III 期臨床試驗。因此，我們繼續將其視為投資組合，所以我們希望將其保留為投資組合揭露，我們預計這將在 2018 年初進行。

Our next question comes from the line of Cory Kasimov with JPMorgan.

我們的下一個問題來自摩根大通的 Cory Kasimov。

So Ian, you alluded to more questions on BD, and I do in fact want to follow up with another bigger picture question on this front. So recognizing this is all still quite fresh, but does the recent progress and substantial derisking on the triple front impact how the company thinks about business development going forward in terms of investing outside of CF? In other words, do you have more confidence or perhaps change to the approach to building outside of your core franchise given what's likely more predictable future -- the future track of CF revenues? Or are these kinds of topics that are mutually exclusive?

伊恩，你暗示了關於BD的更多問題，而我確實想就此提出另一個更宏觀的問題。雖然這一切還很新鮮，但最近在三重方面取得的進展和風險的大幅降低是否會影響公司未來在CF以外的投資方面對業務發展的看法？換句話說，考慮到未來更可預測的趨勢——CF收入的未來趨勢，您是否更有信心或可能會改變在核心特許經營範圍之外進行業務拓展的方法？或者說，這些話題是互斥的？

Yes, Cory, this is Jeff. That's a great question. I'd sort of give you 2 different types of responses. Let me step back. We've actually been working on what's next after CF, which is one part of your question, for quite high now, for a couple of years, and we sort of view it as a 2-part approach. First of all, what's beyond CF in terms of trends to find disease areas really is, we think, consistent with what we've learned in CF. That is we're really only interested in transformative medicines in serious diseases that we can sell into these specialty areas with relatively low SG&A, which will then allow us to recycle most of our OpEx back into R&D. That's the model, and we're going to stick to that model as we move beyond CF. And then we view internal research and BD as essentially complementary, often even looking at the same diseases using some internal programs and some external programs. And so for instance, we've talked about sickle cell disease as a program that we're interested in because it does fit that profile. We have an internal small molecule program or several of them actually in sickle cell disease. We have our collaboration with CRISPR in sickle cell disease, and we may even look at additional outside programs. So this hybrid combination of inside investment and outside investment is the way we're going to go at this for the majority of diseases. Now with respect to your question about the strengthening financial position and how does that change our perspective, I think the key word that you said, which is the word we use, is confidence. As this financial position strengthens, we have more confidence not only in our balance sheet today, but importantly, in our balance sheet tomorrow. And so that's going to let us, I do believe -- give us a lot more financial firepower, let us do more deals and potentially larger. As Ian said, we're not in the business of buying revenue in 2019 or 2020. We're not going to go out and buy marketed products. But we are very interested in diversifying our earlier-stage pipeline with these kinds of transformative medicines, and I think you can expect more of that as our confidence is growing significantly.

是的，科里，這是傑夫。這是一個很好的問題。我大概會給你兩種不同的答案。讓我退後一步。實際上，我們已經研究了 CF 之後的下一步計劃，這也是你問題的一部分，而且已經研究了相當長一段時間了，大概有兩年了，我們把它看作是一個兩部分的方法。首先，就尋找疾病領域的趨勢而言，我們認為，囊性纖維化以外的領域與我們在囊性纖維化領域所學到的知識是一致的。也就是說，我們真正感興趣的是能夠治療嚴重疾病的變革性藥物，我們可以將這些藥物銷售到這些專業領域，並且銷售、管理及行政費用相對較低，這樣我們就可以把大部分營運支出重新投入研發中。這就是我們的模式，我們將在CF之外的領域堅持這種模式。然後，我們認為內部研究和業務拓展本質上是互補的，甚至經常使用一些內部項目和一些外部項目來研究相同的疾病。例如，我們討論過鐮狀細胞疾病，我們對此很感興趣，因為它符合這個特徵。我們有一個針對鐮狀細胞疾病的內部小分子藥物研發項目，或者說是好幾個這樣的項目。我們在鐮狀細胞疾病方面與 CRISPR 展開了合作，我們甚至可能會考慮其他外部項目。因此，對於大多數疾病，我們將採用內部投資和外部投資相結合的混合方式。現在，關於您提出的財務狀況不斷改善以及這會如何改變我們的觀點的問題，我認為您提到的關鍵字，也是我們使用的關鍵字，就是信心。隨著財務狀況的改善，我們不僅對目前的資產負債表更有信心，更重要的是，對未來的資產負債表也更有信心。因此，我相信這將為我們帶來更多的財力，讓我們能夠達成更多交易，而且交易規模可能會更大。正如伊恩所說，我們2019年或2020年的業務重點不是購買收入。我們不會去購買市面上銷售的產品。但我們非常有興趣透過這類變革性藥物來豐富我們早期研發管線，而且隨著我們信心的顯著增長，我認為你們將會期待更多這樣的藥物問世。

Our next question comes from the line of Carter Gould with UBS.

我們的下一個問題來自瑞銀集團的卡特古爾德。

And congrats, again, on all the progress. I guess to segue to beyond CF, a question for Jeff or David. ClinicalTrials.gov says the VX-150 Phase II study is supposed to readout in 4Q. I guess, one, is that the right time line? And two, how should we be thinking about what you want to see to advance into a Phase III in acute pain?

再次恭喜你們取得的所有進展。我想藉此機會聊聊囊性纖維化以外的話題，問傑夫或大衛一個問題。ClinicalTrials.gov 表示，VX-150 II 期研究預計將於第四季公佈結果。我想問的是，第一，這個時間線是否正確？第二，對於您希望看到的急性疼痛治療​​進入 III 期臨床試驗，我們該如何思考？

Yes, so thanks for asking. Let me, again, just take a step back for those that aren't familiar with VX-150. This is our NaV 1.8 inhibitor. This is a novel mechanism -- pain mechanism. As you know, we recently reported positive Phase II data in osteoarthritis, which was really the first proof-of-concept for this mechanism, frankly, in pain. And what's important here and what we said before is we don't view pain as one disease mechanistically. We actually view it as several different diseases. So there is the inflammatory pain that we saw in osteoarthritis. There's acute pain. There's neuropathic pain, in particular. And what we'd like -- what we are doing at this point, and what we'd like to do is to explore this molecule in all 3 of those. So we have the positive readout in OA. We're currently involved in an acute pain study, which is a bunionectomy study, and we do hope that will readout later this year or next year. And then the third study will be a neuropathic pain study, which will start, I hope, later this year. That takes a little longer, so it will likely be 12 to 14 months more once it starts before we read that out, again, depending on enrollment. Once we have the profile of the molecule, then I think we're in a position to really decide: a, how do we best bring it to patients? Which patients? Do we need a partner for some of these? Obviously, community-acquired pain is not something we're going to do, and how to best monetize it as well for Vertex. And so as we accumulate the profile of the compound, we'll keep you informed with each of these trials, and that will lead to the decision about how to take it forward, which is really your question.

是的，謝謝你的提問。讓我再次為那些不熟悉 VX-150 的人簡單介紹一下。這是我們的NaV 1.8抑制劑。這是一種全新的機制－疼痛機制。如您所知，我們最近公佈了骨關節炎的積極 II 期數據，坦白說，這確實是該機制在疼痛治療方面的第一個概念驗證。重要的是，正如我們之前所說，我們並不把疼痛視為單一的疾病，而應該從機制上理解它。我們實際上將其視為幾種不同的疾病。所以，這裡存在著我們在骨關節炎中看到的發炎性疼痛。劇痛難忍。尤其是神經性疼痛。我們現在想做的事——也是我們正在做的，以及我們想做的，就是探索這種分子在這三種情況下的作用。所以我們在OA中得到了陽性結果。我們目前正在進行一項急性疼痛研究，這是一項拇趾外翻切除術研究，我們希望今年晚些時候或明年能公佈研究結果。第三項研究將是一項神經性疼痛研究，我希望它能在今年稍後開始。這需要更長的時間，因此從開始到公佈結果可能還需要 12 到 14 個月，當然，這也取決於報名人數。一旦我們掌握了分子的特性，我認為我們可以真正決定：a，我們如何才能最好地將其帶給病人？哪些患者？有些專案我們需要合作夥伴嗎？顯然，我們不會允許社區獲得痛苦，而且對於 Vertex 來說，如何最好地將其貨幣化也是一個問題。因此，隨著我們不斷累積化合物的資料，我們會隨時向您通報每次試驗的結果，這將最終決定如何推進這項研究，而這實際上也是您的問題。

And our next question comes from the line of Robyn Karnauskas with Citi.

下一個問題來自花旗銀行的 Robyn Karnauskas。

So given that you spent almost $1 billion on R&D, and I know you said a majority of that is CF, can you quantify right now what percentage is non-CF? And if you're thinking about -- you're starting to think about expanding beyond CF, when do you think the CF spend might begin to taper given that even clinical trials you're running are a little smaller than before? So can you help us understand how you expect the R&D spend to evolve a little bit? And could you see an expansion in the non-CF sooner than what we anticipate?

鑑於您在研發上花費了近 10 億美元，而且我知道您說過其中大部分是 CF，您現在能否量化一下非 CF 的百分比？如果你開始考慮將業務拓展到 CF 以外的領域，考慮到你正在進行的臨床試驗規模也比以前小了一些，你認為 CF 方面的支出什麼時候會開始減少？那麼，您能否幫我們了解一下您預計研發支出將如何改變？您認為非CF領域的擴張速度會比我們預期的更快嗎？

Yes, thanks for the question, Robyn. Some of the, let's say, the numbers I'm about to give you might surprise you a little. So first of all, if you take R&D, let's split it up into R and let's split it up into D. So firstly, R. We have 3 research sites. One of those sites is focused on cystic fibrosis. It is focused on other targets as well, but it is primarily our cystic fibrosis site and they've done excellent work, as you know, out in San Diego. There are 2 other sites that are not focused on CF. So already we're spending well beyond 50% of our research investment beyond CF on disease areas that, again, we've touched on, on this call that are similar to CF. But we have a research strategy that goes beyond CF already, and we've been doing that now for a couple of years. And we hope to start seeing some productive results and taking molecules into the clinics of diseases that you may be familiar with. And they should start to see that maybe later this year and certainly into early parts of next year, coming out of research. So already, if you wanted me to put a percentage on it, because it's tangible, but it's probably around 60% that's beyond CF given how we carve up our research activities. For development, it is a little bit of a different story. And by the way, on the research, we're committed to maintaining that kind of approach. I don't think that's going to change in the near term given we continue to invest in CF. And I'd also say in research, we start to supplement it with external relationships, such as CRISPR and Moderna, and we have an investment there as well. When we look at development, development is principally an investment in cystic fibrosis right now. As you may imagine, we have a full pipeline ranging from Phase IIs, all the way through to Phase IIIs. And so the principal investment in development is actually towards CF, and it goes well beyond just clinical trials as well. There is a heavy support in terms of formulation, manufacturing, medical affairs and regulatory. And so I would say probably 80% of our development spend is toward cystic fibrosis. And again, I don't see the investment in cystic fibrosis tailing off significantly for another 3, 4, maybe 5 years. You have to understand, as we get approval for medicines in 12 and older, we immediately are thinking about how we get approval for medicines in 6 through 11, we're thinking about 2 through 5. We're thinking about how we gather longer-term data and build our registry data to support the long-term outcome of our medicines of treating this disease long term. So we need to maintain that support for the medicines we're creating to treat CF. I do see the investment starting to increase beyond CF, but that would be a function of us creating opportunity. And Jeff just talked you through the pain opportunity, we have to see how that plays out. But you will start to see new ideas come into the clinic, and we'll start investing in those. But they'll be earlier stage, so it won't be a significant spend in the next 2 or 3 years. It would grow as they progress down the pipeline.

是的，謝謝你的提問，羅賓。比如說，我接下來要告訴你的一些數字可能會讓你有點驚訝。首先，如果我們把研發（R&D）分成 R 和 D 兩部分。首先是 R，我們有 3 個研究基地。其中一個網站專注於囊性纖維化。它也關注其他目標，但主要目標是我們的囊性纖維化治療中心，正如你所知，他們在聖地亞哥做了很多出色的工作。還有另外兩個網站並非專注於囊性纖維化。因此，我們已經將超過 50% 的研究投資用於囊性纖維化以外的疾病領域，這些疾病領域，正如我們在這次電話會議中提到的，與囊性纖維化類似。但我們已經制定了超越囊性纖維化的研究策略，而且我們已經這樣做了幾年了。我們希望能夠開始看到一些有成效的結果，並將這些分子應用於您可能熟悉的疾病的臨床治療中。他們應該會開始看到，也許在今年晚些時候，而且肯定會在明年年初，從研究中得出結果。所以，如果你想讓我給出一個百分比，因為它是具體可衡量的，但考慮到我們劃分研究活動的方式，這可能佔 CF 的 60% 左右。對於開發而言，情況則略有不同。順便說一句，在研究方面，我們致力於保持這種方法。鑑於我們將繼續投資CF，我認為這種情況短期內不會改變。而且在研究方面，我們也開始透過與外部機構（例如 CRISPR 和 Moderna）的合作來補充研究，我們也對這些機構進行了投資。當我們審視發展時，就會發現目前的發展主要體現在對囊性纖維化領域的投資。如您所想，我們擁有完整的研發管線，涵蓋從 II 期臨床試驗到 III 期臨床試驗的各個階段。因此，研發方面的主要投資實際上是針對囊性纖維化，而且遠遠超出了臨床試驗的範疇。在配方、生產、醫療事務和監管方面都有強大的支持。因此，我認為我們大約 80% 的研發支出都用於囊性纖維化研究。而且，我認為在未來 3 年、4 年，甚至 5 年內，對囊性纖維化的投入不會大幅減少。你必須明白，當我們獲得 12 歲及以上人群用藥的批准後，我們立即開始考慮如何獲得 6 至 11 歲人群用藥的批准，以及 2 至 5 歲人群用藥的批准。我們正在思考如何收集長期數據並建立註冊登記數據，以支持我們藥物治療這種疾病的長期療效。因此，我們需要繼續支持我們正在研發的用於治療囊性纖維化的藥物。我確實看到投資金額開始超過CF，但這取決於我們能否創造機會。傑夫剛才跟你講解了痛苦帶來的機遇，我們得看看結果如何。但你會看到診所出現新的理念，我們也會開始對這些理念進行投資。但它們還處於早期階段，因此在未來兩三年內不會有大量支出。隨著他們沿著管道前進，它也會增長。

And our next question comes from the line of Ying Huang with Bank of America Merrill Lynch.

下一個問題來自美國銀行美林證券的黃穎。

Maybe a follow-up on the qd KALYDECO you got from Concert. It doesn't sound like it's ready for Phase III when you start the triple combo next year. But once that combo is ready, do you think you'll have to run a head-to-head study versus the b.i.d KALYDECO? You have to show the comparability? And also, do you think FDA would want to see that data? Or you think it's just a completely different, separate study just to get that qd KALYDECO through? And then secondly, maybe for Ian, if I add the Q1 ORKAMBI and then Q2 ORKAMBI revenue, just to highlight for the rest of this year, we're already at high end of your guidance. Does that mean this is still very conservative for the $1.1 billion to $1.3 billion guidance for ORKAMBI?

或許可以跟進一下你從 Concert 那裡得到的 qd KALYDECO。聽起來它還沒有準備好進入第三階段，即使你明年開始三重組合訓練。但是一旦這種組合準備就緒，你認為你需要將其與每日兩次的 KALYDECO 進行直接對比研究嗎？你需要證明其可比性嗎？另外，你認為FDA會想看這些數據嗎？還是你認為這只是一個完全不同的、獨立的研究，只是為了讓 qd KALYDECO 通過？其次，對於 Ian 來說，如果我把 ORKAMBI 第一季和第二季的收入加起來，只是為了突出今年剩餘時間的收入，我們已經達到了您預期的上限。這是否意味著，對於 ORKAMBI 而言，11 億美元至 13 億美元的營收預期仍然非常保守？

Maybe I'll take the first one and Ian will take the second one. Yes, with respect to CTP-656, I would think about it as 2 stages. Stage 1 is really more us accumulating sufficient internal data to be confident both about the efficacy, tolerability, safety and dose. But that's a small set of studies that supplements what Concert has already provided so that we can feel comfortable before we go into Phase III, that we know the profile of the drug and we know the appropriate dose as part of a triple. So we're planning to do those kinds of studies over the next months, as I said. And once we accumulate that data, we'll make a decision about taking that triple with CTP-656 forward. And as I said, I think it's doable, although I'm not promising it because we're just learning about the compound to get that done to be in pivotals next year. Then your question about the FDA is a different question. So I would think about that quite simply as are we going to need a Phase III trial there with the iva, and it's our intention to do that. If we incorporate it into a new triple, we would then run pivotal trials there to get that approved by the FDA. If we already have a triple approved then later on we want to substitute it back, that's a different story. That's probably more of a bioequivalence story. But regardless, we're going to need data, both efficacy and some safety tolerability data and dosing data before we dive into Phase III.

也許我會選第一個，伊恩會選第二個。是的，就 CTP-656 而言，我會將其視為兩個階段。第一階段實際上更多的是累積足夠的內部數據，以便對療效、耐受性、安全性和劑量都充滿信心。但這只是一小部分研究，是對 Concert 已提供的研究的補充，以便我們在進入 III 期臨床試驗之前能夠放心，我們知道了藥物的特性，也知道了作為三聯療法一部分的適當劑量。正如我所說，我們計劃在接下來的幾個月內進行這類研究。一旦我們累積了這些數據，我們將決定是否繼續進行與 CTP-656 的三重試驗。正如我所說，我認為這是可行的，雖然我不能保證一定能做到，因為我們仍在了解這種化合物，以便明年能夠進入關鍵階段。那麼，你關於FDA的問題就是另一個問題了。所以我會簡單地思考一下，我們是否需要對 iva 進行 III 期試驗，而這正是我們的計劃。如果我們將其納入新的三重療法，我們將進行關鍵性試驗以獲得 FDA 的批准。如果我們已經批准了三重認證，之後又想把它換回去，那就是另一回事了。這或許更像是個生物等效性問題。但無論如何，在進入 III 期臨床試驗之前，我們需要數據，包括療效數據、安全性耐受性數據和劑量數據。

And Ying, thanks for the question. So as you saw, we are continuing to reiterate our guidance of $1.1 billion to $1.3 billion for ORKAMBI. But you're correct. If you do the math, we've had a strong first half of the year, and if you double up that revenue rate without growth, it does put you in the mid to slightly in the upper parts of our range. And so I can confirm that we do not anticipate being in the low part of our range. But where we fall in the mid to higher part of the range is a function of a number of things. I would point out that firstly, more acutely in short term, we did note in the prepared remarks that Q2 was benefited by some inventory stocking pre-July 4th holiday. And on ORKAMBI, in particular, it was $10 million. And I know you know how that works, but that means you're taking $10 million out of Q3, adding it to Q2, but that doesn't mean a $20 million difference between Q2 and Q3. And so these things do matter when you're trying to pro rata quarters to try and get a full year run rate. And one of the other things, that we need to see how it plays out. We did see a little bit of a summer slowdown last year, and it was more around compliance of medicine and there was lower compliance, which resulted in less revenues. So we need to see how that plays out. We have a number of programs in place that we're trying to help patients to be more compliant this year, but we do need to see how that plays out. And obviously, something that's really important in terms of where we fall in the range is our launches in the new markets of Ireland and Italy, but also whether we gain reimbursement in countries like France. So where we fall in the range, yes, we don't anticipate being in the low end. Be in the mid end and how we climb up from the mid end is really a function of performance, and that's why we're maintaining our guidance.

穎，謝謝你的提問。正如您所看到的，我們繼續重申對 ORKAMBI 的營收預期，即 11 億美元至 13 億美元。但你說得對。如果計算一下，我們上半年的業績非常強勁，即使不考慮成長，如果將營收成長率翻倍，也能達到我們預期範圍的中上水準。因此我可以確認，我們預計不會處於預期範圍的下限。但是，我們最終處於中高端水平的位置，取決於許多因素。首先，我想指出的是，更確切地說，就短期而言，我們在準備好的發言稿中確實提到，第二季度受益於7月4日假期前的一些庫存積壓。特別是 ORKAMBI 項目，耗資 1000 萬美元。我知道你明白其中的道理，但這意味著你要從第三季度拿出 1000 萬美元，加到第二季度，但這並不意味著第二季度和第三季度之間會有 2000 萬美元的差額。因此，當你試圖按季度比例計算以獲得全年運行率時，這些因素就顯得很重要了。還有一件事，我們需要看看事情會如何發展。去年夏天我們確實看到了一些業務放緩，這主要是由於藥品合規性問題，合規性降低，導致收入減少。所以我們需要看看事情會如何發展。今年我們推出了一系列旨在幫助患者提高依從性的項目，但我們需要觀察這些項目的效果如何。顯然，對於我們能否在市場中佔據有利地位而言，真正重要的因素是我們在愛爾蘭和義大利等新市場的推出情況，以及我們能否在法國等國家獲得報銷。所以，我們預期自己在這個範圍內的位置是，是的，我們預期不會處於低端。保持中游位置，而我們如何從中游位置向上攀升，實際上取決於業績表現，這也是我們維持業績指引的原因。

And our last question comes from the line of Adam Walsh with Stifel.

我們的最後一個問題來自 Stifel 的 Adam Walsh。

I got a couple quick ones. First, for Ian. Just for our modeling purposes, can you break out ORKAMBI U.S. and EU revenues? And then one quickly for Jeff on slide, I believe it's 5, you talked about obtaining worldwide rights to CTP-656, but then you also mentioned other assets related to the treatment of CF. If you could just elaborate on the other assets part. If you're referring to something specifically, let us know.

我快速拍了幾張。首先，給伊恩。為了方便我們進行建模，能否提供 ORKAMBI 在美國和歐盟的收入數據？然後，關於 Jeff 的幻燈片，我記得是第 5 張，你談到了獲得 CTP-656 的全球權利，但你也提到了與 CF 治療相關的其他資產。如果您能詳細說明一下其他資產部分就太好了。如果您指的是具體的事情，請告訴我們。

Adam, it's Stuart here. On the ORKAMBI geographic split, it's approximately 90-10. So of the $324 million globally, we recognized $288 million of that was in the U.S. The balance, $36 million, was international.

亞當，我是史都華。ORKAMBI 地理劃分比例約 90-10。因此，在全球3.24億美元的收入中，我們確認了2.88億美元來自美國。剩餘的3600萬美元來自國際市場。

And then on the CTP-656 on the slide, what we're really talking about is there was some additional IP and of course, knowledge about CTP-656, some additional IP around CF, and we acquired all of it as part of this transaction.

然後，關於幻燈片上的 CTP-656，我們真正想說的是，有一些額外的智慧財產權，當然還有關於 CTP-656 的知識，以及一些關於 CF 的額外智慧財產權，所有這些都是我們透過這筆交易收購的。

And I would now like to turn the call back to Michael Partridge, Vice President of Investor Relations, for any closing remarks.

現在我謹將電話轉回給投資人關係副總裁麥可‧帕特里奇，請他作總結發言。

Thank you for joining us on the call. Second time in 8 days we've spoken to you. We appreciate it. The Investor Relations team is in the office tonight if you have any additional questions. Thank you, and have a good night.

感謝您參加本次電話會議。這是我們8天內第二次與您聯繫。我們很感激。如有任何其他疑問，投資者關係團隊今晚在辦公室。謝謝，祝你晚安。

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a great day.

女士們、先生們，感謝各位參加今天的會議。程式到此結束，各位可以斷開連接了。祝大家今天過得愉快。